He was a clerk to Robert Southwell until he joined the Williamite army. As soon as he was discharged from the army, he worked in the Smock Alley Theatre in Dublin from 1691—1693. According to Wilks's version of the story, he had first acted when his army company put on an amateur Othello, and he was so successful that he took up acting as a career. In 1693, Christopher Rich, manager of Drury Lane, hired him to work in London. The same year, he married Elizabeth Knapton.

In 1698, he was back in Dublin to perform in George Etherege plays, and he was so popular that he, according to his story, had to escape to London, and the next year he began his collaboration of George Farquhar. Farquhar and Wilks were close friends, and the two traveled from Dublin to London together. In 1699, Wilks appeared in Farquhar's The Constant Couple as Harry Wildair. It was a role that became Wilks's signature, and it made him a heartthrob among the young ladies of London. For the rest of his life Harry Wildair would be Wilks's alter ego, and Wilks would appear in the starring roles in Farquhar plays.

At Drury Lane, Christopher Rich ruled the theater with a Machiavellian hand. In 1702, Rich had to choose between Wilks and George Powell, the director of rehearsals. The power struggle went Wilks's way, and Powell left for Lincoln's Inn Fields while Wilks was promoted to director of rehearsals. This put Wilks in a powerful position within the theater, and when the actor's strike occurred in 1706, Wilks was well placed to win. Rich was accused of taking one third of all the actors' profits, and the leading actors walked out for the Queen's Theatre at the Haymarket (now Her Majesty's Theatre). Rich, and his son, John Rich, responded by staging opera and pantomime.

At the Haymarket, Wilks was a star. He took the major roles in 1 Henry IV, Hamlet, Julius Caesar, and The Way of the World. He also debuted Farquhar's The Beaux' Stratagem. In 1709, Wilks, with Cibber, Thomas Doggett, and Anne Oldfield joined Owen Swiny in managing the Haymarket. The next year, the group won their struggle and was brought back to Drury Lane, and in 1711 they became the actor-managers of Drury Lane. Thomas Doggett, according to Colley Cibber's somewhat unreliable memoir, forbade any woman being part of the group of managers, and Owen Swiny decided to return to the Haymarket, and so the remaining actor managers formed a "triumvirate." These three managers had profitable and difficult positions, and it is likely that from 1711 to 1714 the shares of the triumvirate never made less than the fantastic sum of £1,000 a year.

In 1713, Barton Booth replaced Doggett as actor-manager, and in 1714 Richard Steele joined them and got the theatre a royal patent. This patent allowed the company to present Charles Johnson'sThe Country Lasses without a license in 1715, and from then on the patent itself was an extremely valuable commodity. Upon Steele's death in 1729, the three current members of the triumvirate got a one-third share in the patent.

The managers were very busy with the details of production, but they were as busy as actors. Wilks acted one hundred and forty performances in the 1721-2 season, for example, and Wilks rarely toured out of London (with the exception of a single trip to Dublin in 1711). Wilks was one of the mainstays of Drury Lane, both as a manager and, even more, as an attractive male lead. Colley Cibber, whose autobiography portrays himself as a voice of reason and calm, paints Wilks as a vain and tempestuous personality, and it is possible to believe Cibber's complaints about others without believing his praise of himself. Alexander Pope satirized Wilks, along with Cibber and Doggett, in The Dunciad, both versions. William Hogarth depicted Wilks as a man busy making a pantomime play of a jail break while using scripts for Hamlet as toilet paper. The actor managers responded to the increasing move for "spectacle" plays (see Augustan drama for context) and quick productions with low costs, and thus the triumvirate, in particular, was frequently satirized for cheapening the stage.

He died in 1732 in London and was buried in St. Paul's Church, Covent Garden. He had made an exceptional amount of money in his life, but, upon his death, he left his second wife virtually nothing except a share in the Drury Lane patent.